1. Field of the Invention
The present invention relates to inhibitors of immune cell proliferation and function. More particularly the present invention is directed to the use of pp14 as inhibitors of immune cell proliferation and function.
2.Background of the Invention
The human immune system functions to protect the organism from infection and from foreign antigens by cellular and humoral mechanisms. The immune system consists of a complex organization of many types of lymphocytes, and macrophages or other antigen-presenting cells. These agents regulate each other by means of multiple cell-cell interactions and by elaborating soluble factors, including lymphokines and antibodies, that have autocrine, paracrine, and endocrine effects on immune cells. Disorders of the regulation of this system may result in uncontrolled proliferation of immune cells and eventually to malignancy, uncontrolled response to foreign antigens or organisms leading to allergic or inflammatory diseases, aberrant immune responses directed against host cells leading to organ damage and dysfunction, or generalized suppression of the immune response leading to severe and recurrent infections.
Interleukin 1 (IL-1) is a peptide cytokine secreted by a range or variety of cell types including accessory cells of the immune system, the antigen presenting cells, and which has a variety of functions including an involvement in the activation of immune system T-cells. Cells secreting IL-1 include monocytes present in the circulating blood, macrophages found in interstitial fluid, and dendritic cells.
It now appears established that IL-1 is a central mediator of inflammatory reactions and is important in the pathogenesis of chronic inflammatory diseases, of which rheumatoid arthritis (RA) is one example. Evidence for this has been derived from a variety of experimental approaches and may be summarized thus:
1. Prostaglandins and leukotrienes are mediators of inflammatory reactions, hence non-steroidal anti-inflammatory drugs, which inhibit cyclooxygenase and prostaglandin synthesis, are useful therapeutically in such conditions. IL-1 mobilizes free arachidonate, the precursor of prostaglandins and leucotrienes, by activating phospholipases, and also induces cyclooxygenase.
2. IL-1 stimulates binding of T-cells to endothelial cells, thought to be the first step in their influx into joints.
3. Injection of recombinant IL-1 into joints causes an influx of inflammatory cells, followed by a loss of proteoglycan from the cartilage.
Treatment of allergies and autoimmune diseases has been based on modalities which are toxic to immune cells, that inhibit production of antibodies, or inhibit the effects of mediators of the immune response, such as histamine. Over the past several years many soluble lymphokines which regulate the immune system have been characterized. Drugs which allow manipulation of the production of function of such factors would be of use in the treatment of autoimmune diseases and perhaps in the treatment of diseases resulting from uncontrolled proliferation of immune cells.
It is now becoming widely accepted that IL-1 (both IL-1 alpha and IL-1 beta) are important mediators of inflammatory responses. IL-1 appears to directly cause cartilage breakdown in knee joints, and may be central in the pathogenesis of rheumatoid arthritis. An inhibitor may, therefore, be of importance in treatment of this disease. It is of interest that pp14 is a natural product present at elevated levels in the peripheral circulation early in pregnancy, peaking around week 9-10, and there are reports in the literature that there is a marked improvement in some sufferers with rheumatoid arthritis in the first trimester of pregnancy. Similar reports of an improvement of patients with chronic asthma in the first trimester of pregnancy can also be found in the published literature. Chronic asthma is an inflammatory disease, and although IL-1 has not yet been implicated in its etiology, this remains a possibility.
As pp14 appears early in pregnancy, it may be associated with the process of implantation and in maintaining the early conceptus which may be particularly prone to immune rejection by the maternal immune system. It is possible that pp14 could be of utility in the treatment of early miscarriage, which may relate to immune phenomena.
Pregnancy is a normal state in which at least one aspect of the immune response--reaction to foreign antigens--is suppressed in regard to paternal antigens expressed by the fetus. It is rational, therefore, to seek natural inhibitory regulators of the immune response in the tissue or bloodstream of pregnant women. The expression of a variety of proteins is induced to high levels during pregnancy. One of these, pp14, is a major secretory protein of decidual tissue, where it comprises about 10% of the total soluble protein.